Prevalence, definition, and etiology of cesarean scar defect and treatment of cesarean scar disorder: A narrative review

Abstract Background Cesarean scar defects (CSD) are caused by cesarean sections and cause various symptoms. Although there has been no previous consensus on the name of this condition for a long time, it has been named cesarean scar disorder (CSDi). Methods This review summarizes the definition, prevalence, and etiology of CSD, as well as the pathophysiology and treatment of CSDi. We focused on surgical therapy and examined the effects and procedures of laparoscopy, hysteroscopy, and transvaginal surgery. Main findings The definition of CSD was proposed as an anechoic lesion with a depth of at least 2 mm because of the varied prevalence, owing to the lack of consensus. CSD incidence depends on the number of times, procedure, and situation of cesarean sections. Histopathological findings in CSD are fibrosis and adenomyosis, and chronic inflammation in the uterine and pelvic cavities decreases fertility in women with CSDi. Although the surgical procedures are not standardized, laparoscopic, hysteroscopic, and transvaginal surgeries are effective. Conclusion The cause and pathology of CSDi are becoming clear. However, there is variability in the prevalence and treatment strategies. Therefore, it is necessary to conduct further studies using the same definitions.

We used the search terms 'cesarean scar defect,' 'cesarean scar syndrome,' 'isthmocele,' and 'uterine niche' to find and collect articles the PubMed database for articles published in the PubMed database up to December 2022. In this review, we present the definition, frequency, and etiology of CSD and clarify the pathophysiology and surgical treatment of symptomatic CSD. Additionally, we propose a treatment algorithm for secondary infertility in women with symptomatic CSD.

| PRE VALEN CE AND DEFINITI ON OF C SD
According to recent review articles on CSD, the prevalence of CSD ranges between 24 and 70% using transvaginal ultrasound (TVS) and 56 and 84% using contrast-enhanced sonohysterography. 8,26,27 Because there are various definitions of CSD, it is not surprising that there are variations in its prevalence. De Vaate et al. defined CSD when the depth was >1 mm, 10  ity with a depth of >5 mm. 30 Other researchers have studied CSD characterized by a hypoechoic lesion in the anterior wall of the lower uterine segment without a clear definition. 6,19,24,31,32 As a result, Jordans et al. defined the criteria of CSD as a depth of at least 2 mm through a consensus using the modified Delphi procedure involving 15 gynecological experts who were members of the European niche taskforce. 33 CSD size is also important because as the CSD increases, AUB and uterine rupture during labor trials after CS also become frequent. 34,35 Furthermore, it is important to evaluate the timing of the menstrual cycle. Our previous report revealed that the prevalence of AUB in women with cesarean scar syndrome was during the follicular (48%) and ovulatory (42%) phases of the menstrual cycle, in contrast to the luteal phase (12%). 11 Therefore, during the mid-follicular phase, fluid collection in the CSD is more frequent than that of the luteal phase. This indicates that CSD may be overlooked on TVS examination if observed during the luteal phase.
TVS is the most commonly used technique for diagnosis. 11 The definition of CSD is based on the value measured by TVS. 33 On the other hand, several studies were conducted by magnetic resonance imaging (MRI) or hysteroscopy. [36][37][38] MRI can uniformly evaluate the size and shape of CSD and the whole of the pelvis; however, TVS is limited by acoustic shadow and inter-rater reliability. Hysteroscopy can provide information on CSD directly, such as the surface of CSD and the presence of an endometrium or a polyp. Therefore, it makes sense to use either MRI or hysteroscopy for research. However, in our study, TVS was deemed enough as the minimal information required for diagnosis, which is the depth of CSD, would be available with this technique. Furthermore, diagnosis using TVS makes economic sense in routine clinical practice.

| Multiple CS
Many papers demonstrated that multiple CS was a major risk of CSD. 6,27,28,39 Osser et al. also demonstrated that myometrial thickness at the level of the isthmus was 8.3, 6.7, and 4.7 mm in women who had one, two, and at least three CS procedures, respectively, although it was 11.6 mm in women who had only vaginal delivery. 39 Cesarian scar defect was detected in 61%, 81%, and 100% of women who underwent one, two, and three CS procedures, respectively. 39 In another prospective cohort study, CSD was found to have developed in 35%, 63%, 76%, and 88% of women with 0, 1, 2, and 3 CS, respectively. 28

| Cervical dilatation
Active labor and cervical dilatation were significant risk factors for CSD, especially cervical dilatation >5 cm. 13,26,27 Vikhareva et al. showed that the odds ratio of a large CSD compared to 0 cm cervical dilatation was 4.4 (95% CI, 0.7-28.5), 26.5 (95% CI, 4.3-161.8), and 32.4 (95% CI 6.1-171.0) at 1-4, 5-7, and 8 cm or more cervical dilatation, respectively. 40 If the station of the presenting part of the fetus at CS was at the pelvic inlet, it was also a risk factor for a large CSD compared to that below the pelvic inlet. 40 Emergency CS also contributed to CSD formation when compared to elective CS. 41 However, some studies have shown that emergency CS was not an independent risk factor for CSD. 28,30

| Uterine closure technique
The single-layer closure technique for the myometrium during CS is associated with a higher risk of CSD than the double-layer closure procedure. 26,30,42 Roberge et al. also showed that double-layer closure with an unlocked first layer was a significant association with thicker residual myometrial thickness (RMT); furthermore, if a double-layer closure was conducted with a locked first layer, there was no significant difference compared with single-layer closure in either RMT. 43 Ceci et al. demonstrated that continuous single-layer closure contributed to a larger defect compared with interrupted sutures. 44 This has been described in the Discussion section of their paper as follows: the ischemic condition of the myometrium negatively affected the healing of cesarean scars. 44 In a systematic review and meta-analysis, Qayum et al. concluded that a double-layer closure contributed to a thicker RMT and lower incidence of dysmenorrhea than a single-layer closure. 45 Vikhareva et al. suggested that a low level of hysterectomy during CS is more frequently associated with CSD development and that cervical tissue attenuates the healing of cesarean scars when included in the closing tissue. 40 They also demonstrated that a low hysterectomy level during CS was significantly associated with a higher incidence of large CSD in a randomized, single-blinded trial. 35 Additionally, Vervoort et al. described low incisions through cervical tissue, including mucus-producing glands, which prevented the healing of the cesarean wound. 46

| Pelvic adhesion
Adhesion of the vesicouterine pouch 18 months after CS was an independent risk factor for CSD according to the results of the univariate logistic regression analysis. 41 Vervoort et al. also described that counteracting forces on the uterine scar by adhesion formation between the uterine scar and the abdominal wall might impair wound healing and develop the formation of CSD. 46 Hayakawa  As described above, CSD is considered to occur depending on the situation and procedure at the time of CS. Although CSD cannot be avoided in some cases, an iatrogenic component might be associated with the development of CSD. Therefore, in the future, it will be desirable to establish a valid CS method to prevent CSDi development.

| SYMP TOMS A SSO CIATED WITH C S D AND ITS NOMEN CL ATURE
Abnormal genital spotting was observed in approximately 30% of women with CSD at 6-12 months after CS. 46 A prospective study by van der Voet et al. showed the relationship between CSD and postmenstrual spotting. 9,39 According to this report, 13 (28.9%) of 45 women with CSD, detected using gel instillation sonography (GIS) at 12 months after CS, had postmenstrual spotting. In contrast, in 29 women without CSD, only 2 (6.9%) had postmenstrual spotting (odds ratio [OR], 5.48; 95% confidence interval [CI], 1.14-26.48).
When a large CSD was classified as a residual myometrial thickness (RMT) of <50% of the adjacent myometrium detected by GIS like Ofili-Yebovi et al., 47 women with large CSD had postmenstrual spotting more frequently than women without large CSD (OR, 6.1; 95% CI, 1.94-26.70). 9 A recent systematic review and meta-analysis by Murji et al. 34 also demonstrated a strong and consistent association between patients with CSD and AUB. Furthermore, they showed that the most common descriptor of CSD-associated AUB was "brown discharge." Wang et al. showed that the prevalence of postmenstrual spotting in 207 women with CSD, dysmenorrhea, chronic pelvic pain, and dyspareunia was 63.8%, 53.1%, 39.6%, and 18.3%, respectively. 6 A combination of these symptoms was unique. Our previous study showed that women with dysmenorrhea were included in women with AUB, and women with chronic pelvic pain were included in women with dysmenorrhea. 11 These events indicate that there is an order in which symptoms appear and that this condition is progressive. These results indicate a significant association between CSD and these symptoms. 41 Isolated or combined symptoms are expressed as niche-related symptoms or symptomatic isthmoceles. 48,49 Morris advocated calling these symptoms cesarean scar syndrome. 50 Since the term describing this condition was not unified, a task force was established to avoid confusion under these conditions. 51 This task force, which comprised experts with experience in the field, provided results using the electronic Delphi method. Therefore, this condition was termed cesarean scar disorder (CSDi). This task force also defined the diagnostic definition of CSDi as a consensus among experts. However, some points must be considered during the diagnosis. First, the cause of AUB should be ruled out according to the International Federation of Gynecology and Obstetrics classification system (PALM-COEIN). 51 Symptoms must be confirmed in at least three menstrual cycles before diagnosis. These symptoms also need to develop and worsen after CS to qualify for CSDi. Based on this study, this review refers to this condition as CSDi.

| HIS TOPATHOLOGY OF C S D IN WOMEN WITH C S D I
Morris first explored the microscopic findings of CSD. 52 This report showed congested endometrium above a scar (61%), polyp formation (16%), lymphocytic infiltration (65%), residual suture material (92%), capillary dilatation (65%), free red blood cells in the endometrial stroma of the scar (59%), fragmentation and breakdown of the endometrium of the scar (37%), and adenomyosis confined to the scar (28%) in a series of 51 hysterectomy specimens.
However, these findings were obtained from patients who did not desire fertility. Donnez demonstrated that muscle fiber density was significantly lower compared with adjacent myometrium and the presence of endometriosis (21%) in 38 patients with CSDi who underwent laparoscopic repair of the defect. 53 AbdullGaffar et al. 21 reported histological findings of CSD obtained by hysterectomy and hysteroscopic resection. Fibromuscular stroma with thick blood vessels was observed in all cases. They also described differences between hysteroscopically resected CSD and hysterectomy specimens. Although there was obscured or unidentified luminal and mucosal hemorrhage in hysteroscopic isthmocele, 56% of patients had luminal hemorrhagic debris or extravasated red blood cells in the mucosal stroma of CSD. 21 Regarding hemorrhage from CSD, Tanimura et al. also showed using hysteroscopy that hemorrhage occurs from CSD. 54 Our group studied histopathological findings of issues obtained from CSD lesions in women who underwent laparoscopic resection due to CSDi. 55 This study demonstrated that the proportion of endometrium present on the surface of CSD was lower in women with CSDi than in women with non-CSDi (22% vs. 62%, respectively). The presence of adenomyosis was also detected (43%) in CSD lesions among women with CSDi. Furthermore, immunohistochemical analysis indicated that chronic inflammation occurred in CSD. These studies suggest that there is a lack of healthy and normal endometrium on the surface of CSD in women with CSDi. Instead, fibrotic tissue with thick blood vessels was observed. Furthermore, minor hemorrhages and chronic inflammation often occur in CSD. Piriyev et al. 56 also reported adenomyosis in 12 (42.9%) patients and fibrosis in 9 (32.1%) patients. Collectively, fibrosis and adenomyosis are considered the main histological findings of CSD.

| DECRE A S ED FERTILIT Y IN WOMEN WITH C S D I
Does CS affect subsequent fertility? Kjerulff et al. 57 showed that the subsequent birth rate after CS was 15% lower than after vaginal birth. From the point of view of assisted reproductive technology (ART), Vissers et al. 58 demonstrated that live birth rates were significantly lower in women with a previous CS than in women with a previous vaginal delivery in an analysis involving 1317 women.
In a systematic review and meta-analysis, Gurol-Urganci, et al. 59 revealed that CS had a significant negative effect on subsequent pregnancy rates (risk ratio, 0.91; 95% CI, 0.87-0.95) compared with vaginal delivery. In contrast, they also demonstrated different conclusions in a population-based cohort study, in which CS had none or slightly negative effects on future fertility if the study was conducted only among low-risk primiparous women. 60 Although it seems inconsistent, it is reasonable based on the CSD risk. As mentioned above, high-risk pregnancies are significantly associated with CSD. Therefore, in the low-risk group, there was little impact on fertility following CS.
However, the pathophysiological reasons why CS leads to decreased fertility remain unclear. Florio et al. described that the persistence of blood in CSD deteriorated mucus and sperm quality, obstructed sperm passing through the cervix, and eventually affected the implantation of the embryo. 7 According to the histopathology findings mentioned above, chronic inflammation can be considered as a cause. Hsu et al. 61 reported that bacterial colonization is more frequent in women with secondary infertility due to CSD.
Microorganisms may be present because of the retention of blood in CSD and contribute to chronic inflammation. Our group demonstrated that the frequency of chronic endometritis in women with CSDi was significantly higher than that in the general infertile population. 62 Additionally, we showed that higher levels of inflammatory cytokines (tumor necrosis factor-a and interleukin-1b) in women with CSDi were detected in the uterine cavity compared to women with a history of CS but without symptoms of CSDi. Bi et al. 18 showed, using correlation analysis, that levels of inflammatory factors (tumor necrosis factor-a, interleukin-1b, and interleukin-6), size of uterine scar diverticulum, and myometrial thickness at uterine scar were significantly correlated with subsequent infertility. These chronic inflammatory conditions within the CSD and pelvic cavity can impair embryonic implantation. Florio et al. 7 reported that the persistence of accumulated blood deteriorated mucus and sperm quality.

| PHARMACOLOG IC AL TRE ATMENT FOR AUB AND DYS MENORRHE A IN WOMEN WITH C S D I
Gynecological symptoms, such as AUB and spotting between menstruations, can be treated with medical management, such as oral contraceptives or a levonorgestrel intrauterine system (LUS). [64][65][66] However, there are not enough studies regarding pharmacological treatment for gynecological symptoms. Therefore, a study regarding the effectiveness of Chinese herbal medicine is underway. 67 In addition, hormone therapy has an ovulation-suppressing effect and cannot be used to treat secondary infertility. Therefore, it is necessary to consider the following ART and surgical therapy for the treatment of secondary infertility.

| ART FOR S ECONDARY INFERTILIT Y IN WOMEN WITH C S D I
Assisted reproductive technology has become an integral part of infertility treatment. Lawrenz et al. 68  showed that the administration of the GnRH agonist, leuprolide acetate, for 3 months prior to the embryo transfer cycle was effective in women with CSDi. This method was inspired by an ultra-long protocol in patients with endometriosis. 70 Since the histopathology of CSD is characterized by endometriosis, their protocol is considered reasonable. 52,55,71 Although ART can have some effects on infertile women with CSDi, our previous report demonstrated that the pregnancy rate following typical treatment, including ART for infertile women with CSDi, was inferior to operative treatment. 11 Baldini et al. 72 reported no association between CSD and cesarean scar pregnancy (CSP) in patients undergoing in vitro fertilization; however, day 5 transfer at the blastocyst stage might be superior to day 3 embryo transfer with regard to preventing CSP.
As mentioned above, there are several reports on ART treatment for women with CSDi, although the number of such reports is insufficient. To date, there are no reports of ART being superior to surgical therapy. Therefore, surgical therapy should be considered first, or in cases of no conception, even after the transfer of a good embryo.

| L APAROSCOPIC SURG ERY IN WOMEN WITH C S D I
Laparoscopic repair of CSD in a patient with CSDi was first described by Jacobson et al. 73 as a case report. However, the true pioneers of laparoscopic repair of CSD were Donnez et al., 74 whose group demonstrated three cases of laparoscopic repair and later published a series on the same. 53,75 Many authors then showed the effectiveness of laparoscopic repair. 65,71,[76][77][78][79][80][81][82][83][84][85][86][87] According to previous reports, there are two points that we have to pay attention to in laparoscopic surgery for CSDi ( Table 1).
The first is how to identify CSD after opening the uterovesical peritoneum and separating the bladder from the uterus. Donnez et al. 74 and Li et al. 76     To date, there have been no reports of uterine rupture in pregnancies following laparoscopic repair.
Based on the above, we believe that the optimal laparoscopic surgery at present is to use a hysteroscope in combination to excise the CSD accurately, suture the wound in two layers, and in some cases, correct the uterine position by suturing the round ligament.

| HYS TEROSCOPI C SURG ERY IN WOMEN WITH C S D I
Fernandez et al. 97  Some reports have shown that RMT was increased by resectoscopic surgery, whereas others did not significantly influence RMT. 71,[98][99][100][101] This difference may be attributed to different procedures of hysteroscopic surgery. In our study, only the inferior edge of the CSD was resected, and the entire isthmus was cauterized using a ball electrode. Therefore, the RMT became thicker after the resectoscopic surgery (Figure 2). Additionally, RMT thickening is a predictor of pregnancy prognosis. 101 Florio et al. 102 reported that the effectiveness of hysteroscopic surgery was superior to hormonal therapy in women with CSDi.
Furthermore, in a randomized controlled study, hysteroscopic surgery was proven to be effective in treating symptoms associated with CSD. 82  there were two cases of perforation during surgery in the severe defect group. 106 Therefore, when the RMT is <2.2 mm, we believe that laparoscopic surgery should be considered.
To date, there are no reports of uterine rupture during pregnancy following hysteroscopic surgery. If a patient undergoes a planned CS, we believe that there is a small risk of uterine rupture in a subsequent pregnancy after hysteroscopic surgery. Unlike laparoscopic surgery, hysteroscopic surgery does not involve anatomical repair.
Therefore, uterine extension due to postoperative pregnancy may decrease RMT. If dehiscence is detected during CS, the trimming technique may have contributed to preventing the recurrence of CSDi. 107 In this technique, the first layer is closed using a modified Gambee suture. This suture technique may contribute to a thicker RMT, even if a thinned myometrium is detected during the CS.
Endometriosis is often detected in the peritoneal cavity of women with CSDi. Therefore, we recommend that hysteroscopic TA B L E 2 Hysteroscopic surgery for CSDi.  To date, all reports on vaginal repair have shown significant effectiveness for symptoms in women with CSDi (Table 3).

Author
Furthermore, some reports have demonstrated that vaginal repair contributes to an increased RMT. However, there is insufficient evidence regarding secondary infertility and subsequent pregnancy outcomes following vaginal repair of CSD. In a systematic review and meta-analysis, Yuan et al. 119 recently reported that hysteroscopic resection is superior to vaginal surgery in terms of blood loss, operative time, and hospital duration. However, there was no significant difference in the effectiveness of AUB and the restoration of RMT.

| CON CLUS ION
Cesarean scar defect was significantly associated with AUB and secondary infertility. Abnormal uterine bleeding is caused by the retention of menstrual blood and minor hemorrhage from the CSD. thin RMT have tended to avoid hysteroscopic surgery, which is generally less invasive than laparoscopic repair. Furthermore, we believe that laparoscopy should be used in combination with hysteroscopic surgery because endometriosis is often a complication in women with secondary infertility due to CSDi. Therefore, based on previous reports, we proposed a treatment algorithm for patients who wish to conceive (Figure 3).
So far, the lack of a definition for both CSD and symptoms due to CSD has led to variability in the frequency of CSD and clinical outcomes of several interventions for women with CSDi. We believe that conducting research using the same definition in the future will contribute to establishing more accurate frequency and treatment methods.

ACK N OWLED G M ENT
We would like to thank Editage (www.edita ge.com) for English language editing.

FU N D I N G I N FO R M ATI O N
Grants in Aid for Scientific Research (KAKENHI; 20K09616) supported this study and the preparation of this manuscript, including English language editing services.

Takashi Murakami is an Editorial Board member of Reproductive
Medicine and Biology and a co-author of this article. To minimize bias, he was excluded from all editorial decision-making related to the acceptance of this article for publication.

F I G U R E 3
Treatment algorithm for secondary infertility in women with cesarean scar disorder. When residual myometrial thickness (RMT) is <2.2 mm, laparoscopic surgery with a hysteroscope is recommended because it is useful to accurately resect the cesarean scar defect (CSD). When RMT is ≥2.2 mm, hysteroscopic correction with laparoscopy is recommended because patients with cesarean scar disorder (CSDi) often have endometriosis. In both ways, the uterus is repositioned by suturing the round ligament to relieve tension on repaired CSD.

H U M A N R I G HT S S TATE M E NT A N D I N FO R M E D CO N S ENT/A N I M A L S TU D I E S
This article does not contain any studies involving human and animal subjects performed by any of the authors.

E TH I C S S TATEM ENT
No ethical approval was needed for this review article.